IDENTIFICATION & SELECTION OF ADULT NEURAL PRECURSORS

鉴别

• 批准号: 6330475
• 负责人: STEVEN Alan GOLDMAN
• 金额: $ 33.73万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330475
• 关键词: biomarker; brain mapping; cell cell interaction; cell cycle; cell differentiation; cell migration; cell population study; cell type; clinical research; human subject; neurogenesis; neurons; neurotrophic factors; prosencephalon; stem cells; tissue /cell culture

DESCRIPTION (Abstract reproduced verbatim): Neuronal precursor cells are distributed throughout the ventricular subependyma, or subventricular zone (SVZ), of the adult vertebrate forebrain. We previously found that adult precursors are more widespread, both spatially and phylogenetically, than the limited instances of adult neurogenesis in vivo might indicate. On this basis, we postulated that neuronal recruitment into the adult brain is restricted not by the distribution of neural precursors, but rather by a failure of the mature brain environment to provide permissive support of neuronal differentiation and survival. The focus of this proposal is to define the distribution, lineage potential and humoral control of the progenitor pools, in the adult human forebrain. Our aim is to elicit neuronal production in the damaged brain, by inducing endogenous precursors to resume neurogenesis, and by providing for the differentiation and survival of their neuronal progeny. To wit,1. What is the distribution of neuronal and uncommitted neural precursors in the adult human SVZ? 2. Can the adult human subependyma be deconstructed into its constituent progenitor phenotvpes? By sorting dissociates of human SVZ after transfection with P/Talphal:hGFP, can neuronal progenitors be harvested specifically, and in high yield? Can their mitotic potential be retained after neuronal commitment? Can their transmitter phenotypes be modulated? 3. Is there a distinct phenotype of neural stem cell, as rigorously defined as a self-replicating multipotential progenitor, in the adult human VZ? Using the early neural regulatory sequences for nestin a musashi proteins, coupled to GFP as reporters of phenotype, can such uncommitted progenitors be selected from adult human brain tissue? Can these cells be directed towards neurogenesis by humoral neurotrophins? 4. Is there a distinct class of hippocampal progenitor? Are adult human hippocampal progenitors multipotential or neuronally-committed? Is their native lineage potential more restricted than that of SVZ progenitors? We intend to learn enough about the biology and selective harvest of adult human neuronal progenitors to establish an operational basis for their therapeutic use. Our goal is to utilize these cells for neuronal replacement within the damaged brain, whether by activating endogenous progenitors, or implanting exogenous cells. If this work is successful, we may soon need to consider how best to train newly generated networks of replacement neurons and glia to assume lost functions, in diseases as diverse as stroke, trauma, and the neurodegenerations.

描述（逐字复制摘要）：神经元前体细胞是 分布于室管膜下或室管膜下区 (SVZ)成年脊椎动物的前脑。我们之前发现成年人 前体在空间上和生物学上都比 有限的成年体内神经发生的例子可能表明。在此基础上， 我们假设，进入成年大脑的神经元募集受到限制， 通过神经前体的分布，而是通过成熟的 脑环境提供神经元分化的容许支持， 生存本提案的重点是定义分布、谱系 潜力和体液控制的祖细胞池，在成年人 前脑我们的目标是在受损的大脑中引发神经元的产生， 诱导内源性前体恢复神经发生，并通过提供 它们的神经元后代的分化和存活。为了见证，1.是什么 成年人神经元和非定向神经前体细胞的分布 SVZ？2.成人室管膜下能被解构成它的组成部分吗 祖先表型？通过分选转染后的人SVZ解离物 使用P/TGFa 1：hGFP，可以特异性地收获神经元祖细胞， 高收益？在神经元定型后，它们的有丝分裂潜能能否保留？ 它们的递质表型可以被调节吗？3.是否有一种独特的表型 神经干细胞，严格定义为自我复制的多潜能细胞， 在成年人VZ中的祖细胞？利用早期的神经调节序列 对于nestin a Musashi蛋白，偶联GFP作为表型报告基因， 这种未定型的祖细胞可以从成人脑组织中选择吗？可以 这些细胞被体液神经营养素引导向神经发生？4.是 有一个独特的海马体祖先吗是成年人的海马 祖细胞是多能的还是神经定向的是他们的本土血统 比SVZ祖细胞的潜力更受限制？我们打算学习 足够的生物学和选择性收获成人神经元 祖细胞，以建立其治疗用途的操作基础。我们 目的是利用这些细胞在受损的神经元中进行神经元替代， 大脑，无论是通过激活内源性祖细胞，还是植入外源性 细胞如果这项工作取得成功，我们可能很快就需要考虑如何最好地 训练新生成的替代神经元和神经胶质网络， 功能，在中风，创伤，以及 神经退化